Stroke is the second leading cause of death and a major cause of disability in the world. The current[unreadable] generation of thrombolytic agents, such as tissue-type plasminogen activator (tPA), only benefit a limited[unreadable] number of the potential patients with ischemic stroke, and the development of improved therapies for the[unreadable] treatment of stroke depends upon understanding the unique characteristics of the cerebrovasculature. The[unreadable] limited benefit of tPA may be due in part to unique activities that tPA has in the brain beyond its well[unreadable] established role as a fibrinolytic protease. In particular, animal studies have indicated that tPA interacts with[unreadable] at least two different cellular receptors expressed in the brain, and these associations have been linked to[unreadable] both neurotoxicity and altered blood-brain-barrier function. And while there are clear benefits to patents who[unreadable] receive early thrombolytic treatment, these recently described effects of tPA suggest that there are unique[unreadable] challenges for the use of thrombolytic therapy in ischemic stroke. Ideal treatments for ischemic stroke would[unreadable] simultaneously promote the reestablishment of vascular patency, inhibit the development of cerebral edema,[unreadable] reduce the incidence of hemorrhagic transformation, and provide direct neuroprotection. Our previous[unreadable] studies have shown that the natural inhibitor of tPA in the CNS, neuroserpin, appears to act as a[unreadable] neuroprotective agent that can promote significant neuronal survival and cell recovery after stroke. In[unreadable] addition our studies suggest that antagonism within the CNS of the tPA receptor, the LDL Receptor Related[unreadable] Protein (LRP), dramatically reduces blood-brain-barrier dysfunction following stroke. Thus, this proposal will[unreadable] test the hypothesis that during cerebral ischemia tPA, neuroserpin, and LRP function together within the[unreadable] brain to regulate blood-brain-barrier permeability and neuronal survival. We will investigate the mechanisms[unreadable] of this regulation, and test the hypothesis that targeting these interactions will lead to the development of[unreadable] more effective therapies for the treatment of ischemic stroke. We will also evaluate novel treatments for[unreadable] stroke by combining various thrombolytic and neuroprotective agents, and comparing the efficacy of these[unreadable] combined therapies in murine models of stroke.